Terpenes are a large and structurally diverse family of natural products that range from simple hydrocarbons associated with flavors and fragrances, to complex, highly oxidized polycyclic molecules such as the anti-malarial drug artemisinin, and the anticancer compounds ingenol and taxol. Although terpenes are isolated from natural sources, it can be challenging to translate their biological activity into a practical application. In some cases, the hurdle is low natural abundance; other times, it is the difficulty encountered by chemists seeking to precisely edit a terpene's molecular structure in order to improve its drug-like properties or interrogate its role in modulating disease pathways. The development of concise chemical syntheses of terpenes can transform the ability to use these molecules and their synthetic derivatives as biological probes or as lead compounds for the development of new medicines. Furthermore, these scientific efforts often innovate chemical reactivity or synthetic design concepts.
The natural product ryanodine (1) and its hydrolysis product ryanodol (2) are among the most highly oxidized and synthetically challenging diterpenoids reported to date.

Isolated from the tropical shrub Ryania speciosa Vahl in connection with its insecticidal properties, ryanodine is the namesake ligand of the ryanodine receptors (RyRs), an important family of ion channels that regulate intracellular Ca2+ release and play a critical role in signal transduction. In mammalian cells, these receptors exist in multiple isoforms (RyR1, RyR2, and RyR3) that serve to mediate both movement and cognitive function. Mutations of RyRs are associated with genetic diseases such as malignant hyperthermia and central core disease, while altered expression of RyR2 and RyR3 has been associated with the pathogenesis of neurodegenerative disorders such as Alzheimer's disease. Ryanodine binds with high affinity to the conducting state of RyRs, exerting concentration dependent modulation of Ca2+ release: at nanomolar concentrations, ryanodine locks RyRs in an open, subconductance state, whereas at higher concentrations, ryanodine causes closure of the channels. The deacylated compound ryanodol binds with lower affinity than 1 to mammalian RyRs; however, it still induces a subconductance state and has been reported as a reversible probe of RyR-mediated Ca2+ release in cells.
Since the initial reports describing the isolation of ryanodine from Ryania, a number of congeners (known as ryanoids) that vary in oxidation pattern have been isolated. Whereas ryanodol—the compound obtained by hydrolysis of ryanodine has not yet been isolated directly from a natural source, the closely related compound C3-epi-ryanodol (4) was isolated by Gonzaléz-Coloma from Persea indica.

Indeed, due to their structural similarities, C3-epi-ryanodol (4) was initially erroneously reported to be ryanodol (2); however, the structure of the Coloma-Gonzalez isolate was recently reassigned through the synthetic efforts of Inoue. (M. Koshimizu et al, Angew Chem. Int. Ed. Engl. 55, 2493-2497 (2016)). These subtle differences in structure exert a pronounced effect on RyR-binding: C3-epi-ryanodine (5), prepared from 4, binds 100 fold more weakly to RyRs than 1. (W. Welch et al. Biochemistry 36, 2939-2950 (1997)).

Given the biological importance of the RyRs, the ryanoids have been the focus of both total synthesis and derivatization efforts. (A. Belanger et al. Can. J. Chem. 57, 3348-3354 (1979); P. Deslongchamps et al. Can. J. Chem. 68, 115-126 (1990); P. Deslongchamps et al. Can. J. Chem. 68, 127-152 (1990); P. Deslongchamps et al. Can. J. Chem. 68, 153-185 (1990); P. Deslongchamps et al. Can. J. Chem. 68, 186-192 (1990); M. Nagatomo et al. J. Am. Chem. Soc. 136, 5916-5919 (2014); M. Nagatomo et al. Chemistry 22, 222-229 (2016); K. Masuda et al. Chemistry 22, 230-236 (2016); A. L. Waterhouse, et al. J. Med. Chem. 30, 710-716 (1987); W. Welch et al. Biochemistry 33, 6074-6085 (1994); J. L. Stuko et al. Pharmacol. Rev. 49, 53-98 (1997)). These synthetic efforts, however, include up to 41 steps.
Alternative routes of preparing (+)-ryanodol and ryanodol, as well as derivatives thereof, are needed